Opioids such as morphine or fentanyl effectively relieve severe pain, but are often addictive and can have fatal side effects. The USA is therefore in an opioid crisis with numerous deaths, and the number of opioid addicts is also increasing in Germany. Now, through complex calculations and tests, biomedical scientists have discovered a natural painkiller that could have fewer side effects. The active ingredient from a marine fungus could therefore replace opioids in the long term and alleviate the crisis.
Opioids such as morphine, fentanyl and oxycodone are very effective painkillers. They are often a blessing for seriously ill people in the final stages of life and people with severe chronic pain. However, if used improperly, opioids can also be addictive and lead to fatal side effects such as respiratory arrest. In the USA, the painkillers were heavily advertised for a long time and were mistakenly prescribed even for milder complaints. As a result, almost 645,000 people died from an opioid overdose in the USA between 1999 and 2021, according to figures from the Centers for Disease Control and Prevention (CDC).
Opioids have also become a problem in Germany, especially fentanyl, because it is used to dilute heroin. Fentanyl is fatal at just two milligrams, while heroin is only fatal at 200 milligrams. It therefore easily leads to accidental overdoses. In total, more than 1,000 people died in Germany in 2022 from opioid use. Although governments are trying to contain these crises, many people are dependent on opioids or suffer severe pain because they cannot take opioids. Safer painkillers are therefore urgently needed.
Search for the needle in the haystack
A research team led by Roxana Damiescu from Johannes Gutenberg University Mainz (JGU) has now discovered a possible alternative painkiller. The team used a chemical database with over 40,000 natural products as a starting point. The biopharmaceutical researchers searched for active ingredients that bind to the corresponding opioid receptor and at the same time have the necessary chemical properties to be used as a drug. Using a supercomputer, they first carried out around 750,000 calculations for each substance and determined the ten most suitable active ingredients.
Damiescu and her colleagues then examined these candidates in the laboratory to determine their actual biochemical properties and their safety. Among other things, the researchers analyzed human kidney cells to see whether the active ingredients are harmful in higher concentrations. In further tests, they checked how well the substances bind to the opioid receptors and trigger a reaction there.
Active ingredient from marine fungus could replace opioids
After the tests, one of the ten active ingredients met all the criteria for a potentially safe painkiller: Aniquinazolin B from the marine fungus Aspergillus nidulans. The substance belongs to the class of quinazolinone alkaloids and effectively activated the opioid receptors in the tests, but via different signaling pathways than opioids, as the team reports. Aniquinazolin B therefore has a lower addictive potential. “Our studies indicate that this active ingredient could have a similar effect to opioids, but with significantly fewer side effects,” says Damiescu. The natural product could therefore replace opioids in the future. However, the candidate must first undergo further tests on animals over the next few years to confirm the pain-relieving effect and safe use of the preparation.
Source: Roxana Damiescu (Johannes Gutenberg University Mainz) et al.; ChemMedChem, doi: 10.1002/cmdc.202400213